title: Long-term mequindox treatment induced endocrine and reproductive toxicity via oxidative stress in male Wistar rats.
abstract: Mequindox (MEQ) is a synthetic antimicrobial chemical of quinoxaline 1, 4-dioxide group. This study was designed to investigate the hypothesis that MEQ exerts testicular toxicity by causing oxidative stress and steroidal gene expression profiles and determine mechanism of MEQ testicular toxicity. In this study, adult male Wistar rats were fed with MEQ for 180days at five different doses as 0, 25, 55, 110 and 275mg/kg, respectively. In comparison to control, superoxide dismutase (SOD), reduced glutathione (GSH) and 8-hydroxydeoxyguanosine (8-OHdG) levels were elevated at 110 and 275mg/kg MEQ, whereas the malondialdehyde (MDA) level was slightly increase at only 275mg/kg. Furthermore, in LC/MS-IT-TOF analysis, one metabolite 2-isoethanol 4-desoxymequindox (M11) was found in the testis. There was significant decrease in body weight, testicular weight and testosterone at 275mg/kg, serum follicular stimulating hormone (FSH) at 110 and 275mg/kg, while lutinizing hormone (LH) levels were elevated at 110mg/kg. Moreover, histopathology of testis exhibited germ cell depletion, contraction of seminiferous tubules and disorganization of the tubular contents of testis. Compared with control, mRNA expression of StAR, P450scc and 17β-HSD in testis was significantly decreased after exposure of 275mg/kg MEQ while AR and 3β-HSD mRNA expression were significantly elevated at the 110mg/kg MEQ group. Taken together, our findings provide the first and direct evidence in vivo for the formation of free radicals during the MEQ metabolism through N→O group reduction, which may have implications to understand the possible mechanism of male infertility related to quinoxaline derivatives.
authors.affiliation: National Reference Laboratory of Veterinary Drug Residues and MOA Key Laboratory of Food Safety Evaluation, Huazhong Agricultural University, Wuhan 430070, PR China. awais.dr@gmail.com
authors.forename: Awais
authors.initials: A
authors.lastname: Ihsan
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.forename: Zhaoying
authors.initials: Z
authors.lastname: Liu
authors.forename: Yulian
authors.initials: Y
authors.lastname: Wang
authors.forename: Xianju
authors.initials: X
authors.lastname: Huang
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.forename: Huan
authors.initials: H
authors.lastname: Yu
authors.forename: Hongfei
authors.initials: H
authors.lastname: Zhang
authors.forename: Tingting
authors.initials: T
authors.lastname: Li
authors.forename: Chunhui
authors.initials: C
authors.lastname: Yang
authors.forename: Zonghui
authors.initials: Z
authors.lastname: Yuan
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism; D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011810:Quinoxalines / Q000633:toxicity*; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013047:Specific Pathogen-Free Organisms; D013482:Superoxide Dismutase / Q000378:metabolism; D013737:Testis / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: C545385:Mequindox; D010750:Phosphoproteins; D011810:Quinoxalines; D012333:RNA, Messenger; D011944:Receptors, Androgen; D000098682:Steroidogenic Acute Regulatory Protein; D008315:Malondialdehyde; D000080242:8-Hydroxy-2'-Deoxyguanosine; D015067:17-Hydroxysteroid Dehydrogenases; D013482:Superoxide Dismutase; D003849:Deoxyguanosine; D005978:Glutathione